Avermectin compounds are well known antiparasitic agents useful in animal health, human health and agriculture. The avermectin compounds, and the related milbemycin compounds are prepared micro-biologically and are highly complex organic molecules. See Albers-Schoenberg et al, U.S. Pat. No. 4,310,519 and Chabala et al, U.S. Pat. No. 4,199,569. Avermectin B1 is composed of a mixture, typically 80% a and 20%, of the 25-sec-butyl (B1a) and 25-isopropyl (B1b) side chains. Thoughout the specification avermectin B1 will refer to this mixture. The minor structural difference has been found to have very little effect on the chemical reactivity or biological activity of the compounds. The natural stereochemistry of the 13-position substituent of the avermectins is .alpha., with the oxygen atom below the plane of the ring.
Inversion of the 13-position from the .alpha. to the .beta. configuration produces a highly desirable functionality, useful in the preparation of 13-epi compounds and active as anthelmintic agents. Prior efforts at inverting the 13-position stereochemistry were complex, multi-step syntheses that resulted in poor yields and mixtures of isomers. See Mrozik et al, J. Med. Chem., 32 pg 375-381 (1989). Pending U.S. patent application Ser. No. 698,874, filed May 13, 1991, describes a process for preparing 13-.beta.-compounds whereby a 13-.alpha. leaving group is displaced by tetraalkylammonium nitrate followed by reduction of the resultant nitrate ester with zinc in the presence of acid to yield the 13-.beta. configuration. However, this process employs expensive reagents that are not readily available and conversion to the nitrate ester is low. Additionally, reduction of the nitrate ester is a difficult process not amenable to scale up. Efforts at preparing the 13-.beta. compounds also have not been successful when traditional epimerization procedures were attempted such as the well-known Mitsunobu inversion reaction. See Mitsunobu, Synthesis pg 1-28 (1981) and Hughes et al, J. Am. Chem. Soc., 110 pg 6487-6491 (1988). See also Cainelli et al, Tetrahedron Lett. 26 pg 3369-3372 (1985) and Cainelli et al, Tetrahedron 41 pg 1385-1892 (1985) for a general description of an inversion process involving nucleophilic displacement promoted by nitrate ions. Of all of the procedures attempted, the inversion of the 13-position stereochemistry is most readily accomplished as described below with the highest yields of any such processes.